Aging causes complex changes in physiological functions including decline of glucose metabolism and immune defense responses. Extending the lifespan and delaying aging would provide the best defense against these age-related complications. There are known genes mutations and dietary interventions i.e. calorie restriction (CR) that protect from age-related diseases, can delay aging and also extend maximum longevity. Unfortunately, the detailed mechanism providing these benefits is not determined yet. Our most recent data of circulating serum miRNAs identified families of miRNAs that change with age in N animals, but remain stable in Ames dwarf (df/df) mice and mice subjected to CR. microRNA 146a-5p (miR-146a- 5p)is one of the miRNA species that increases with aging in normal mice, while it stays unchanged in long-living df/df mice. As part of the innate immune system, miR-146a-5p regulates Toll-like receptor signaling pathways, regulating cytokine-mediated inflammatory responses and insulin signaling pathway. Importantly, our newest preliminary data showed age- dependent accumulation of senescent cells promotes over-expression and secretion of this pro- aging miRNA. Based on these observations our overall hypothesis is that that age-related accumulation of senescent cells enhances miR-146a-5p expression, causing insulin resistance and chronic systemic inflammation through silencing of the IRAK1/TRAF6 and deregulation of PI3K/AKT and NF?B. To test our hypothesis we propose three specific aims: Aim 1.Determine the tissue/cell-specific source of pro-aging miR-146a-5p and cause of upregulation of this exosomal miRNA during aging. Aim 2. Determine the mechanistic role of miR-146a-5p in insulin sensitivity and inflammation during aging. Using miR-146a mimic or inhibitor we will either increase or inhibit the expression level of this miRNA in long-living df/df and normal mice to investigate the regulatory role of this pro-aging miRNA on IRAK1/TRAF6 and NF?B signaling pathways. Aim 3. Investigate if targeting senescent cells with senolytic agents suppresses expression of miR-146a-5p in old animals and improves inflammatory status and insulin action in old or high fat-fed mice.